The goal of this project is to obtain pharmacologicaly acceptable reagents that can modify sites on sickle cell hemoglobin to change its aggregating and gelling behavior. It seem likely that only amine-containing residues in hemoglobin are reasonable candidates for covalent modification with reagents mild enough to be pharmacologically approved. Exploratory experiments with aspirin have demonstrated that its acetyl group is transferred to sickle cell hemoglobin. However the extent of transacetylation is not large enough to decrease sickling adequately. Aspirin, however, is only the simplest example, the prototype, of the broad class of acylsalicylates. Increases in acylating activity, and hence of antisickling effect, should be attainable by appropriate modification of either the leaving group, the salicylate, or of the acyl function. Several new classes of alternative aspirins, i.e. of modified acylsalicylates, are being synthesized. One class consists of monosalicylates with a wide variety of functional groups on the acyl entity, designed to obstruct amine-containing side chains that may be at contact interfaces of hemoglobin tetramers in the sickle fiber, or to increase the intrinsic solubility of hemoglobin. A second category of reagents comprises anionic, double-headed aspirins (bridged bis-salicylates) that have a high probability of being bound within the cationic Beta-cleft of hemoglobin and of forming a rigin dovalent molecular clamp between the Beta-subunits so that their geometry is out of register for aggregation. These substances should modify the aggregation characteristics of sickle hemoglobin and sickling behavior in erythrocytes.